Entry of enveloped viruses into host cells is poorly understood. This is especially true for viruses which enter cells in a pH-independent manner. Included within this class is the human immunodeficiency virus and most other retroviruses. It appears however that similar mechanisms are utilized by many viruses based on the conserved features of the viral envelope proteins, suggesting a potential site for therapeutic intervention. Specific cellular receptors are utilized by the viral envelope proteins during infection. Only a few cellular proteins which mediate viral entry have been described, and there is at present no obvious common feature of these proteins which distinguishes them as viral receptors. Clearly use of a system in which there is genetic variability in the receptor such that functional and nonfunctional variants exist may permit the requisite features of a viral receptor to be defined. Rous sarcoma virus (RSV)represents such a system. In RSV there is not only genetic variation of the receptors but also a number of closely related envelope proteins (i.e. subgroups) which each interact with a different receptor. The receptor for one of the RSV subgroups has recently been isolated. It is an extremely small membrane glycoprotein consisting in its simplest form of a 72 amino acid glycosylphosphatidylinositol-liked glycoprotein. Within the extracellular region of this receptor is a protein motif closely related to the low density lipoprotein receptor (LDLR) ligand binding repeat. This motif has a role in protein-protein interaction in many of the other proteins in which it occurs. Therefore it is likely it may have a similar role in the receptor-envelope protein interaction. Given the extremely small size of this receptor it will be possible to perform a detailed molecular analysis of this receptor protein. The overall goal of this project is to define the specific sequences or features of the RSV subgroups A receptor protein which mediate retroviral entry into the host cell. To accomplish this goal, three specific aims will be pursued during the tenure of this rant. They are: 1) Characterize the gene, mRNA, and proteins in cells permissive and those restrictive for subgroup A RSV entry. 2) Define regions of the receptor which interact with the virus to facilitate entry. 3) Characterize the normal function or ligands for the RSV(A) receptor and determine if normal function relates to athe receptor's role in viral uptake.